Funding MDS Research

Benjamin Ebert, M.D., Ph.D.

2017 Funding Recipient

PPM1D is a promising new therapeutic target for MDS

EvansMDS Discovery Research Grant 2017

PROJECT SUMMARY

Therapy-related MDS (t-MDS) is among the most feared consequences of chemotherapy or radiation for solid tumors. Often occurring years after treatment for a solid tumor, t-MDS is often an aggressive disease that is very difficult to treat. Existing therapies have relatively little efficacy in t-MDS and survival is poor.

We have found that mutations in a gene, PPM1D, are very common in t-MDS, and that the mutations result in a new drug target for the treatment of t-MDS. These mutations enable hematopoietic stem cells to survive during chemotherapy or radiation treatment, relative to normal cells, leading to a pre-malignant expansion of PPM1D-mutated cells. Over the subsequent years, with the acquisition of additional mutations, the pre-malignant PPM1Dmutant clone can evolve into t-MDS.

In our preliminary studies, we have determined that the PPM1D mutations cause increased levels and activity of PPM1D. PPM1D is a phosphatase, an enzyme, that regulates the DNA damage response pathway. Importantly, increased activity of PPM1D in the mutant cells can be targeted therapeutically. Although a PPM1D inhibiting drug does not exist, a tool compound that can be used in the laboratory, but does not have sufficient drug-like properties to be used clinically, can be used to validate PPM1D as a therapeutic target for the treatment of t-MDS.

In this application, we propose to make the first models of t-MDS using genome engineering to introduce mutations into the PPM1D gene and the other genes that cooperate in the evolution of t-MDS. These models are critical for determining whether inhibition of PPM1D would be an effective treatment for t-MDS, and would be needed to test candidate drugs before they enter clinical trials.

Our second major aim is to understand better how the mutations in PPM1D lead to t-MDS. Our preliminary data indicate that the mutations always remove the same portion of the protein, which removes a signal that targets PPM1D for degradation. We propose to examine the mechanistic basis for this degradation and determine how PPM1D is regulated.

In aggregate, these studies will not only inform the biology PPM1D mutations, but will also lay the groundwork for the development of new therapies that target PPM1D for the treatment of t- MDS